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Psychol Med. 2018 Aug;48(11):1890-1899. doi: 10.1017/S0033291717003415. Epub 2017 Nov 29.

Genetic risk of major depressive disorder: the moderating and mediating effects of neuroticism and psychological resilience on clinical and self-reported depression.

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Division of Psychiatry,University of Edinburgh,Royal Edinburgh Hospital,Edinburgh EH10 5HF,UK.
Section of Clinical Psychology,University of Edinburgh,Medical Quad,Teviot Place,Edinburgh EH8 9AG,UK.
Department of Psychology,University of Edinburgh,7 George Square,Edinburgh EH8 9JZ,UK.



Polygenic risk scores (PRS) for depression correlate with depression status and chronicity, and provide causal anchors to identify depressive mechanisms. Neuroticism is phenotypically and genetically positively associated with depression, whereas psychological resilience demonstrates negative phenotypic associations. Whether increased neuroticism and reduced resilience are downstream mediators of genetic risk for depression, and whether they contribute independently to risk remains unknown.


Moderating and mediating relationships between depression PRS, neuroticism, resilience and both clinical and self-reported depression were examined in a large, population-based cohort, Generation Scotland: Scottish Family Health Study (N = 4166), using linear regression and structural equation modelling. Neuroticism and resilience were measured by the Eysenck Personality Scale Short Form Revised and the Brief Resilience Scale, respectively.


PRS for depression was associated with increased likelihood of self-reported and clinical depression. No interaction was found between PRS and neuroticism, or between PRS and resilience. Neuroticism was associated with increased likelihood of self-reported and clinical depression, whereas resilience was associated with reduced risk. Structural equation modelling suggested the association between PRS and self-reported and clinical depression was mediated by neuroticism (43-57%), while resilience mediated the association in the opposite direction (37-40%). For both self-reported and clinical diagnoses, the genetic risk for depression was independently mediated by neuroticism and resilience.


Findings suggest polygenic risk for depression increases vulnerability for self-reported and clinical depression through independent effects on increased neuroticism and reduced psychological resilience. In addition, two partially independent mechanisms - neuroticism and resilience - may form part of the pathway of vulnerability to depression.


depression; generation Scotland; mediation; moderation; neuroticism; polygenic risk; resilience

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